Schizophrenia is a frightening and heart-rending malady which affects about 15 out of 10,000 persons annually in the United States and is characterized by a group of disorders that produces severe disturbances in cognition, reality testing, mood, interpersonal relations, social and work function. Schizophrenia affects men and women equally and the symptoms associated with this dreadful disorder can largely be divided into the positive and the negative categories. The negative symptoms consist of behavioral deficits such as blunting of emotions, language deficits, and lack of energy while the positive symptoms include auditory and visual hallucinations, delusions, and bizarre behavior. The critical roles that the neurotransmitters dopamine and serotonin play in the disease is becoming increasingly clear with the isolation and cloning of the five receptors for the former and fourteen for the latter. Drugs currently used in the treatment of schizophrenics, which are known as neuroleptics or antipsychotics, are designed to relieve the diverse symptoms of the disease so that the patient can function as close to a normal human being as possible and also to delay or prevent possible relapse. Conventional or `classical' antipsychotics such as chlorpromazine (Thorazine) and haloperidol (Haldol). while are quite effective in relieving the positive symptoms of schizophrenia, are beset not only with undesirable albeit reversible side effects such as restlessness, stiffness, and tremor but also with a more serious one as tardive dyskinesia which is not fully reversible. With the advent of the newer and so-called `atypical antipsychotics' such as clozapine (Clozaril), olanzapine (Zyprexa), and aripiprazole (Abilify), the side effects associated with the classical antipsychotics have been alleviated to a large extent. These drugs, in contrast to the `classical' antipsychotics, are highly effective in relieving both the positive and the negative symptoms of schizophrenia and elicit their response by blocking both the dopamine D2 as well as the serotonin 5-HT2A receptors in the pertinent regions of the brain. However these drugs produce different types of side effects such as sometimes fatal agranulocytosis (clozapine) and significant but undesirable weight gain (olanzapine). Therefore, there is a tremendous need for new and potent antpsychotics with drastically reduced or even void of the deleterious side effects mentioned above and this grant proposal describes the synthesis and biological evaluation of novel atypical antipsychotics of the types A and B shown below. R N N Type A: X = O; Type B: X = S X Schizophrenia is an insidious and frightening malady which affects about 15 out of 10,000 persons annually in the United States and is characterized by a group of disorders that produces diverse disturbances in cognition, reality testing, mood, interpersonal relations, social and work function. PUBLIC HEALTH RELEVANCE Schizophrenia affects men and women equally and the symptoms associated with this dreadful disorder can largely be divided into the positive and the negative categories. The negative symptoms consist of behavioral deficits such as blunting of emotions, language deficits, and lack of energy while the positive symptoms include auditory and visual hallucinations, delusions, and bizarre behavior. Conventional or `classical' antipsychotics such as chlorpromazine (Thorazine) and haloperidol (Haldol). while are quite effective in relieving the positive symptoms of schizophrenia, are beset not only with undesirable albeit reversible side effects such as restlessness, stiffness, tremor, and tardive dyskinesia. With the advent of the newer and so-called `atypical antipsychotics', such as clozapine (Clozaril) and olanzapine (Zyprexa), and aripiprazole (Abilify), the side effects associated with the classical antipsychotics have been alleviated to a large extent. However these drugs produce different types of side effects such as sometimes fatal agranulocytosis (clozapine) and significant but undesirable weight gain (olanzapine). Therefore, there is a great need for new and potent antpsychotics with drastically reduced or even void of the deleterious side effects mentioned above, and this grant proposal focuses on the development of such new atypical antipsychotics. [unreadable] [unreadable] [unreadable]